Lysophosphatidic acid (LPA) is a physiologically active phospholipid which is present in a living body. By binding to specific G-protein-coupled receptors (LPA1, LPA2, LPA3, LPA4, LPA5 and LPA6), LPA transduces signals into cells and modulates the proliferation, the differentiation, the survival, the migration, the adhesion, the infiltration and the morphogenesis of cells. Further, it is known that LPA is involved in diseases accompanied with fibrosis in various organs.
It has been reported that in the liver, LPA stimulates the proliferation or contraction of stellate cells which play an important role in the process of hepatic fibrosis, and stimulates the migration of myofibroblasts (see Non-Patent Documents 1, 2 and 3).
It has been reported that in the kidney, the production of LPA or the expression of LPA1 is enhanced in mice with unilateral ureteral ligation as renal fibrosis animal models, and that the renal fibrosis is suppressed by LPA1 deficiency or administered of an LPA receptor antagonist (see Non-Patent Documents 4 and 5).
Regarding the lung, it has been reported that bronchoalveolar lavage fluids from patients with idiopathic pulmonary fibrosis have an increased LPA concentration, and that LPA1 is most expressed receptor in fibroblasts having an important role in the process of pulmonary fibrosis and LPA induces the migration of fibroblasts. Further, it has been reported that the LPA1 deficiency or the administration of an LPA receptor antagonist suppresses fibrosis in intratracheally bleomycin administered mice as pulmonary fibrosis animal models (see Non-Patent Documents 6 and 7).
Concerning the skin, it has been reported that skin fibrosis is suppressed by the LPA1 deficiency or the administration of an LPA receptor antagonist in mice which are subcutaneously administered with bleomycin as scleroderma models (see Non-Patent Document 8).
It is also known that LPA is involved in immunological or inflammatory diseases. It has been reported that LPA stimulates the migration of human monocyte, and is involved in the proliferation or infiltration of T cells. Further, it has been reported that synovial cells of rheumatoid arthritis patients express LPA receptors and migrate or produce IL-6 and IL-8 by LPA stimulation, and that these actions are inhibited by an LPA receptor antagonist (see Non-Patent Documents 9, 10 and 11).
In addition, it has been reported that LPA and LPA1 are involved in the development of neuropathic pain (see Patent Document 12), that LPA causes extracted urethra specimens and prostatic specimens to contract and the intraurethral pressure to increase and is thus involved in urologic diseases (see Patent Document 1), and that LPA is involved in cancer-related diseases by stimulating the infiltration of cancer cells, by stimulating the proliferation of ovary cancer cells, or by stimulating the proliferation of prostate cancer cells (see Non-Patent Documents 13, 14 and 15).
Based on these reports, a medicament that antagonizes the LPA receptors (in particular, the LPA1 receptor) is considered to be useful for the prevention and/or the treatment of diseases accompanying fibrosis, immunological or inflammatory diseases, central or peripheral nervous system diseases, urologic diseases and cancer-related diseases, etc.
On the other hand, Patent Documents 2 to 23 and Non-Patent Documents 5, 7, 8 and 16 disclose ([1,1′-biphenyl]-4-yl)acetic acid derivatives, Patent Document 17 discloses (2′-methoxy-[1,1′-biphenyl]-4-yl)acetic acid derivatives, and Patent Document 19 discloses 3-chloroisothiazole derivatives as compound having an antagonistic function on LPA receptors, there is no disclosure of the compounds according to the present invention.